Development of antimicrobial peptides (AMPs) as novel therapeutics has garnered interest in view of the increasing threat of multiple drug resistant micro-organisms coupled with the lack of new synthetic antimicrobial chemicals. Antimicrobial peptides play a key role in the functioning of a host's innate defense system against infections in most mammalians (Boman H G et al Annu. Rev. Immunol. 13:61-92). The potential therapeutic applications of AMPs are characterized by their broad-spectrum antibacterial activity. It would be extremely difficult for multi-drug/fungicide resistant micro-organisms to evolve resistance against AMPs that disrupt the microbial membrane, since it would necessitate fundamental alterations in the lipid composition of the bacterial membranes.
Diseases caused by fungi, bacteria and viruses are of major concern to human health and to agricultural produce due to the heavy crop losses incurred by fungal infestations. Chemical drugs and solutions used to evade diseases cause extensive deterioration in environment quality and a rise in resistant organisms. Therefore, there is an increase in the need for safe and effective antimicrobial agents with expanding number of immunocompromised patients at risk for invasive fungal infections. AMPs (antimicrobial peptides) have been considered as novel therapeutics in combating the increasing incidence of antibiotic resistance in pathogenic microbes and several examples are undergoing clinical trials.
Nature provides the answer in the form of antimicrobial peptides that are not only lethal to a broad spectrum of pathogens but also have a unique low tendency for resistance development. A variety of antimicrobial peptides and proteins have been isolated from virtually all the kingdoms and phyla including plants, microbes, insects, animals and humans. Rational design of novel non-natural AMPs can be targeted to enhance stability, potency and specificity towards selected microbes. Short sequence length of these AMPs facilitates design of synthetic genes, and incorporation into plants through genetic engineering. These are unique candidate target peptides (probiotic), which are often half the size of natural counterparts (10-20 Amino Acids) and are active at low concentrations without toxicity to host tissues. In many cases, synthetic analogs of natural antimicrobial peptides offer even more target specificity, increased efficacy at lower concentration, and reduced degradation by plant proteases than their natural counterparts.
In a research study ‘Design and engineering strategies for synthetic antimicrobial peptides’ (Prokaryotic Antimicrobial Peptides 2011, pp 81-98) A. Tossi reveals an important feature in the mode of action of AMPs is their dynamic interaction with biological membranes, which involves properties of these peptides such as, surface hydrophobicity and polarity, charge, structure, and induced conformational variations which are often intimately interconnected; hence engineering peptides to independently adjust any one property in particular is not an easy task. However, solid-phase peptide synthesis allows the use of a large repertoire of non-proteinogenic amino acids that can be used in the rational design of peptides to finely tune structural and physicochemical properties.
In Indian Patent Application No. 1010/DEL/2006, the preparation and antimicrobial activities of hexapeptides, which offer an improved means for the treatment and prevention of fungal and bacterial infections is disclosed. The development of these peptides provides for the treatment and control of opportunistic fungal infections. However, no references to the stability of the hexapeptides are provided, which is integral to the systemic administration and functioning of the peptides. Furthermore, synthetic peptides disclosed in the Indian application include the use of non-natural amino acids such as ornithine which increases the cost of synthetic peptide production, and renders genetic engineering procedures impractical.
Though natural AMPs have many antimicrobial attributes, several studies have exposed their potential limitations as therapeutic agents. A significant number of natural AMPs are large however, exhibit moderate antimicrobial activity. Moreover, their production cost is high. In addition, many natural AMPs lose their antimicrobial activity at higher salt concentrations. These characteristics have substantially weakened their pharmaceutical development as new therapeutic agents. Thus, successful development of novel AMPs as future therapeutics requires identification of short AMPs demonstrating strong antimicrobial activity, high stability and minimal toxicity to host tissue.
Synthetic antimicrobial peptides are being viewed as promising alternatives as novel therapeutics in combating increasing incidence of antibiotic resistance in pathogenic microbes in humans. In addition, AMPs have been shown to be active against plant pathogens. Several AMPs are active against both human and plant pathogens. AMPs that are active against a broad range of pathogens are more desirable and need to be tested against different pathogens to confirm their activity.
In view of a pending need in the art to develop antimicrobial peptides having broad spectrum activity along with favorable characteristics for administration in a subject, the present inventors have devised an anti-microbial composition comprising novel synthetic peptides having activity against bacterial and fungal pathogens.